2. It includes- Introduction to Pathology Cellular response to
stress and noxious stimuli Cellular adaption to stres Cell injury
and cellular death Causes of cell Injury Morphology of cell and
tissue injury
3. Introduction to Pathology Pathos- suffering and logos- study
Pathology is study of the structural, biochemical and functional
changes in cell, tissues, and organ that underlie diseases. Study
of pathology is divided into General pathology Systemic
pathology
4. General pathology it concerned with the common reaction of
cells and tissues to injurious stimuli. Four aspects forming core
of pathology- 1.Etiology or Cause- 2. Pathogenesis 3. Morphological
Changes 4. Functional derangements and clinical
manifestations.
5. Etiology Origin of a disease, including the underlying
causes and modifying factors It may be Genetic ( inherited
mutations,) Acquired (infections, nutritional , chemical etc)
Etiology refers to why disease arises
6. Pathogenesis Steps in the development of disease It refers
to sequences of cellular, biochemical and molecular events that
follows the exposure of cells or tissues to an injurious
agent.
7. Morphological Changes Structural alteration in the cells or
tissues that are either characteristic of diseases or diagnostic of
an etiological process. Molecular analysis reveals genetic
differences that predict the behavior of tumor and their
responsiveness to therapies.
8. Functional derangements and clinical manifestations It is
the end results of genetic, biochemical and structural changes in
cells and tissues. It leads to signs and symptoms of disease as
well as its progress ( clinical course and outcome) All forms of
disease start with molecular or structural alterations in
cells.
9. Cellular responses to stress and noxious stimuli Cells
normally maintain a steady state called homeostasis in which the
intracellular milieu is kept within a fairly narrow range of
physiologic parameters. As cells encounter physiologic stresses or
pathologic stimuli, they can undergo adaptation, achieving a new
steady state and preserving viability and function. The principal
adaptive responses are hypertrophy, hyperplasia, atrophy, and
metaplasia.
10. If the adaptive capability is exceeded or if the external
stress is inherently harmful, cell injury develops. Within certain
limits, injury is reversible, and cells return to a stable baseline
If the stress is severe, persistent and rapid in onset, it results
in irreversible injury and death of the affected cells
11. Cell death is one of the most crucial events in the
evolution of disease in any tissue or organ It results from diverse
causes, including ischemia (lack of blood flow), infections,
toxins, and immune reactions Cell death also is a normal and
essential process in embryogenesis, development of organs, and the
maintenance of homeostasis
12. Cellular Adaption to Stress Adaptations are reversible
changes in the number, size, phenotype, metabolic activity, or
functions of cells in response to changes in their environment
Physiologic adaptations- these are responses of cells to normal
stimulation by hormones or endogenous chemical mediators (hormone-
induced enlargement of the breast and uterus during pregnancy)
Pathologic adaptations are responses to stress that allow cells to
modulate their structure and function and thus escape injury
13. Hypertrophy Hypertrophy is an increase in the size of cells
resulting in increase in the size of the organ. In hypertrophy
there are no new cells, just bigger cells containing increased
amounts of structural proteins and organelles Hypertrophy occurs
when cells have a limited capacity or no capacity to divide.
Hypertrophy can be physiologic or pathologic
14. Causes of Hypertrophy Response to demand for increased
workload or from endocrine stimulation Increased functional demand
Muscle hypertrophy in body builder Heart muscle hypertrophy in
chronic hemodynamic over load Hormone induced- Physiological
enlargement of uterus during pregnancy Compensatory hypertrophy
most commonly seen in the paired organs. If one organ of the pair
e.g. kidney is damaged or removed the other organ increases in size
to compensate for the loss
15. Physiological hypertrophy of uterus during pregnancy
16. Pathologic cellular hypertrophy Cardiac enlargement that
occurs with hypertension or aortic valve disease
17. Gross Appearance The tissue or organ is larger and heavier
than normal Microscopically The size of cells is increased
indicated by a decrease in the number cells in each microscopic
field Significance and Results Compensatory hypertrophy increases
the function of organ and tissues. If the workload continues to
increase decomposition and organ failure will occur
18. Mechanism of hypertrophy
19. 2. Switch from adult to fetal or neonatal form. eg. Muscle
hypertrophy- isoform to isoform. 3. Reexpression of gene that
present during early developmental stages. eg. ANP
20. Hyperplasia Hyperplasia characterized by an increase in
cell number because of proliferation of differentiated cells and
replacement by tissue stem cells Hyperplasia is an adaptive
response in cells capable of replication May occur concurrently
with hypertrophy and often in response to the same stimuli
Hyperplasia can be physiologic or pathologic
21. Physiologic hyperplasia Hormonal hyperplasia Proliferation
of the glandular epithelium of the female breast at puberty and
during pregnancy Compensatory hyperplasia Residual tissue grows
after removal or loss of part of an organ. eg. partial hepatectomy
Bone marrow in blood cell deficiency acute bleeding and
hemolysis.
22. Pathological Hyperplasia Caused by excessive hormonal or
growth factor stimulation Endometrial hyperplasia due to hormonal
imbalance between estrogen and progesterone. Benign prostatic
hyperplasia Viral infection like papilloma virus causes skin wart
and mucosal lesions composed of mass of hyperplastic
epithelium.
23. Mechanism of hyperplasia it is results of growth factor
driven proliferation of mature cells and In some cases, by
increased output of new cells from tissue stem cells.
24. Atrophy Shrinkage in size of the cell by the loss of cell
substance is known as atrophy. When a sufficient number of cells
are involved, the entire tissue or organ diminishes in size,
becoming atrophic. Atrophy may be physiological or
pathological.
25. Physiological atrophy It is common during normal
development. Atrophy of embryonic structure such as notochord and
thyroglossal duct during fetal development. Decrease in uterus size
after paturition.
26. Pathological atrophy 1. Disuse atrophy- Due to decreased
workload or inactivity - atrophy of muscles occurs when a plaster
cast is applied to a broken limb. 2. Denervation atrophy Neurogenic
or neurotropic atrophy due to loss of innervation. Atrophy of
laryngeal muscles (roaring) occurs due to degeneration of left
recurrent nerve.
27. 3. Diminished blood supply ( ischemia) seen in slowly
developing arterial occlusive diseases Brain atrophy Senile atrophy
due to progressive developing atherosclerosis. 4.Nutritional
(starvation) atrophy Caused by starvation or malnutrition Seen in
protein calorie malnutrition (marasmus)- due to utilization of
muscle protein as an energy source
28. 5. Loss of endocrinal stimulation- After menopause loss of
estrogen stimulation physiological atrophy of endometrium , vaginal
epithelium and breast. 6. Pressure atrophy Due to mild, continuous
pressure on cells and tissues causing obstruction of blood supply.
Enlarging benign tumor causing atrophy of surrounding uninvolved
tissues.
29. Brain atrophy
30. Mechanism of atrophy The mechanisms of atrophy consist of a
combination of decreased protein synthesis and increased protein
degradation in cells. Protein synthesis decreases because of
reduced metabolic activity. The degradation of cellular proteins
occurs mainly by the ubiquitin-proteasome pathway Atrophy is also
accompanied by increased autophagy, with resulting increases in the
number of autophagic vacuoles.
31. Gross Appearance The affected organ is decrease in size,
soft and flabby and may appear pale. Microscopic Appearance The
cells are smaller in size and number. The cytoplasm contains
membrane-bound vacuoles which contain fragments of cell components
(organelles) Some of the cell debris with in autophagic vacuoles
resist digestion and persist as residual bodies ( eg.- lipofuscin
granules Chronic inflammation in many organs is associated with
atrophy
32. Metaplasia Metaplasia is a reversible change in which one
differentiated cell type (epithelial or mesenchymal) is replaced by
another adult cell type. Metaplasia arise by reprogramming of stem
cells to differentiate along a new pathway rather than a phenotypic
change (transdifferentiation) of already differentiated cells.
33. Types of metaplasia Columnar to squamous metaplasia- Most
common type of metaplasia Site- Respiratory tract in response to
chronic irritation like smokers Excretory duct of salivary glands,
pancreas or bile duct- Due to stone Deficiency of vitamin A (
retinoic acid)
34. Squamous to columnar- Barrett esophagus- Squamous
epithelium is replaced by intestinal like columnar cells.
Connective tissue metaplasia- Formation of cartilage, bone or
adipose tissues in tissues that normally do not contain these
elements. Myositis ossificans- bone formation in muscle ( after
intramuscular hemorrhage)
35. Significance Metaplasia is an adaptive response in which
cells sensitive to a particular stress are replaced by more
resistant cell type. Metaplastic tissue returns to normal if the
cause is removed, however cartilage and bone remain permanently.
Metaplasia may result in reduced functions or increased propensity
for malignant transformation.
36. CELL INJURY Cell encounters many stresses as a result of
changes in their internal and external environments Different
injurious stimuli affect many metabolic pathways and cellular
organelles
37. Causes of cell injury 1.Hypoxia (deficiency of oxygen) :
Ischemia or anemia 2. Physical agent: burns, deep cold, radiation,
electric shock and mechanical trauma 3. Biological agents: viruses,
bacterial toxins, fungi and parasites 4. Chemical agents and drugs
5. Endogenous toxins :uremia, jaundice and diabetic ketosis 6.
Immunologic reactions (hypersensitivity) 7. Nutritional imbalance
:PEM, starvation, obesity, DM and other substances and vitamins
deficiency 8. Genetic abnormalities :Down syndrome & sickle
cell anemia 9. Aging
38. MORPHOLOGY OF CELL AND TISSUE INJURY Reversible Injury The
two main morphologic correlates of reversible cell injury are
cellular swelling and fatty change Cellular swelling is the result
of failure of energy-dependent ion pumps in the plasma membrane
Fatty change occurs in hypoxic, toxic or metabolic injuries and
manifested by appearance of small/large lipid vacuoles in the
cytoplasm
39. Morphology of Reversible Injury Cellular swelling It causes
some pallor (compression of capillaries), increased turgor, and
increase in weight of the organ Small, clear vacuoles within the
cytoplasm represent distended and pinched-off segments of the ER
This pattern of nonlethal injury is sometimes called hydropic
change or vacuolar degeneration
40. Fatty changes Manifested by the appearance of lipid
vacuoles in the cytoplasm Principally encountered in cells
participating in fat metabolism (hepatocytes, myocardial cells) and
is also reversible
41. Intracellular changes associated with reversible injury 1.
Plasma membrane alterations such as blebbing, blunting, or
distortion of microvilli, and loosening of intercellular
attachments. 2. Mitochondrial changes : swelling and appearance of
phospholipid-rich amorphous densities . 3. Dilation of the ER with
detachment of ribosomes and dissociation of polysomes. 4. Nuclear
alterations, with clumping of chromatin. 5. Cytoplasm may contain
phospholipid masses, called myelin figures, derived from damaged
cellular membrane.
42. A. Normal kidney tubules with viable epithelial cells B.
Early (reversible) ischemic injury showing surface blebs, increased
eosinophilia of cytoplasm, and swelling of occasional cells C.
Necrotic (irreversible) injury of epithelial cells, with
fragmentation and nuclear loss and leakage of contents
43. Irreversible Injury Persistent or excessive injury, causes
cells to pass the nebulous point of no return into irreversible
injury and cell death Two phenomena characterize irreversibility 1.
Inability to correct mitochondrial dysfunction (lack of oxidative
phosphorylation and ATP generation) even after resolution of the
original injury 2. Profound disturbances in membrane function
Injury to lysosomal membranes results in enzymatic dissolution of
injured cell, which is culmination of injury progressing to
necrosis
44. Necrosis Local death of cells followed by morphological
changes in the surrounding living tissue Causes of cell necrosis
-viruses, ischemia, bacterial toxins, hypersensitivity, and
ionizing radiation Associated with Loss of membrane integrity and
leakage of cellular contents culminating in dissolution of cells It
results from degradative action of enzymes on lethally injured
cells Leaked cellular contents often elicit local host reaction
called inflammation, that attempts to eliminate the dead
cells.
45. Morphology of Necrosis Characterized by changes in
cytoplasm and nuclei of the injured cells Cytoplasmic changes
Necrotic cells show increased eosinophilia. Cells may have more
glassy, homogeneous appearance,b/f the loss of glycogen particles.
Myelin figures are more prominent in necrotic cells than during
reversible injury. When enzymes have digested cytoplasmic
organelles, the cytoplasm becomes vacuolated and appears
moth-eaten.
46. Electron microscopy Necrotic cells are characterized by
discontinuities in plasma and organelle membranes Marked dilation
of mitochondria with the appearance of large amorphous densities
Disruption of lysosomes, and intracytoplasmic myelin figures
Nuclear changes Assume one of three patterns, all due to breakdown
of DNA and chromatin
47. Karyolysis fading of basophilia of the chromatin , it
reflects loss of DNA due to endonuclease. Pyknosis characterized by
nuclear shrinkage and increased basophilia; Chromatin condenses
into a solid shrunken mass . Karyorrhexis , pyknotic nucleus
undergoes fragmentation In 1 to 2 days, the nucleus of dead cell
may completely disappear Electron microscopy reveals profound
nuclear changes culminating in nuclear dissolution
48. Features of Necrosis and Apoptosis Features Necrosis
Apoptosis Cell size Enlarged(Swelling) Reduced( shrinkage) Nucleus
Pyknosis Karyorrhexis Karyolysis Fragmentation into nucleosome size
fragments Plasma membrane Disrupted Intact, Altered structure,
especially orientationof lipid Cellular content Enzymatic
digestion: may leak out of cell Intact: may be released in
apoptotic bodies Adjacent inflammation frequent No Physiologic or
pathologic role Invariably pathologic Often physiologic, means of
eliminating unwanted cells; may be pathologic after some forms of
cell injury
49. Reversible Injury Generalized swelling Cell Membrane Blebs
Myelin Figures ER swelling and Dispersion of ribosome Mitochondrial
swelling with small densities Autophagy by lysosomes Clumping of
nuclear chromatins Irreversible Injury Generalized swelling Cell
Membrane Blebs Myelin Figures ER swelling and Dispersion of
ribosome Mitochondrial swelling with large amorphous densities
Nucleus 1. Pyknosis 2. Karyolysis 3. Karyorrhexis
50. Fates of necrotic cells Necrotic cells may persist for some
time or may be digested by enzymes and disappear Dead cells may be
replaced by myelin figures, which are either phagocytosed by other
cells or further degraded into fatty acids These fatty acids bind
calcium salts, which may result in the dead cells ultimately
becoming calcified
51. Patterns of Tissue Necrosis Coagulative Necrosis Underlying
tissue architecture preserved for several days. The affected
tissues take on a firm texture. Injury denatures both structural
proteins and enzymes, thereby blocking the proteolysis of the dead
cells. Eosinophilic, anucleate cells may persist for days or
weeks.
52. Leukocytes recruited to site of necrosis, and dead cells
are digested by action of lysosomal enzymes of leukocytes. The
cellular debris is then removed by phagocytosis. Coagulative
necrosis is characteristic of infarcts(areas of ischemic necrosis)
in all of the solid organs except the brain.
53. Liquefactive Necrosis Seen in focal bacterial or,
occasionally, fungal infections . Microbes stimulate accumulation
of inflammatory cells and the enzymes of leukocytes digest
(liquefy) the tissue. Dead cells completely digested, transforming
the tissue into a liquid viscous mass.
54. Gangrenous necrosis The tissue in this case have undergone
ischaemic cell death and coagulative necrosis followed by
liquifactive action of putrefactive organisms When coagulative
pattern is dominant the process is termed dry gangrene. eg lower
limb When the liquifactive action of the bacteria is more
pronounced it is called wet gangrene
55. Caseous necrosis Most often in foci of tuberculous
infection Grossly, the caseous material resembles clumpy cheese,
hence the name caseous necrosis The cause of necrosis in TB is
hypersensitivity reaction caused by protein content of the cell
wall of Mycobacterium tuberculosis
56. Necrotic focus appears as a collection of fragmented or
lysed cells with an amorphous granular pink appearance in the usual
H&E- stained tissue. Unlike with coagulative necrosis, the
tissue architecture is completely obliterated and cellular outlines
cannot be discerned The area of caseous necrosis is often enclosed
within a distinctive inflammatory border Appearance is
characteristic of a focus of inflammation known as granuloma
57. Fat Necrosis Focal areas of fat destruction, typically
resulting from release of activated pancreatic lipases into the
substance of the pancreas and the peritoneal cavity This occurs in
calamitous abdominal emergency known as acute pancreatitis In this
disorder, pancreatic enzymes that have leaked out of acinar cells
and ducts liquefy the membranes of fat cells in the peritoneum, and
lipases split the triglyceride esters contained within fat
cells
58. Grossly Released fatty acids combine with calcium to
produce chalky white areas (fat saponification) Microscopically
Foci of necrosis contain shadowy outlines of necrotic fat cells
with basophilic calcium deposits, surrounded by an inflammatory
reaction
59. Fibrinoid necrosis Special form of necrosis, visible by
light microscopy Usually in immune reactions in which complexes of
antigens and antibodies are deposited in the walls of arteries
Deposited immune complexes, together with fibrin that has leaked
out of vessels, produce a bright pink and amorphous appearance on
H&E preparations called fibrinoid The immunologically mediated
diseases (polyarteritis nodosa) in which this type of necrosis is
seen
60. The wall of the artery shows a circumferential bright pink
area of necrosis with protein deposition and inflammation
